Estrogens refer to a group of endogenous and synthetic hormones that are important for and used for tissue and bone maintenance. Estrogens are endocrine regulators in the cellular processes involved in the development and maintenance of the reproductive system. The role of estrogens in reproductive biology, the prevention of postmenopausal hot flashes, and the prevention of postmenopausal osteoporosis are well established. Estradiol is the principal endogenous human estrogen, and is found in both women and men.
The biological actions of estrogens and antiestrogens are manifest through two distinct intracellular receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Endogenous estrogens are typically potent activators of both receptor subtypes. For example estradiol acts as an ERα agonist in many tissues, including breast, bone, cardiovascular and central nervous system tissues. Selective estrogen receptor modulators commonly act differently in different tissues. For example, a SERM may be an ERα antagonist in the breast, but may be a partial ERα agonist in the uterus, bone and cardiovascular systems. Compounds that act as estrogen receptor ligands are, therefore, useful in treating a variety of conditions and disorders.
Prostate cancer is one of the most frequently diagnosed noncutaneous cancers among men in the US and is the second most common cause of cancer deaths with 241,740 new cases and 28,472 deaths expected in 2012 in the United States. Up to 30% of patients with prostate cancer that undergo primary treatment by radiation or surgery will develop metastatic disease within 10 years of the primary treatment. Approximately 50,000 patients a year will develop metastatic disease, which is termed metastatic CRPC (mCRPC).
Patients with advanced prostate cancer undergo androgen deprivation therapy (ADT), either by luteinizing hormone releasing hormone (LHRH) agonists, LHRH antagonists or by bilateral orchiectomy.
Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castration resistant prostate cancer (CRPC) one of the major causes of which is incomplete castration. Castration, as defined by orchiectomy, results in total testosterone (T) levels much lower than 50 ng/dL, the cut off set over 40 years ago based on the lower limit of detection of those older assays. Current T assays are more accurate and measuring free (unbound) T is a better reflection of the T available to androgenic tissues including prostate cancer. Although 20 ng/dL total T has been suggested as a new cut off to achieve for effective castration, in men treated with LHRH, the mean chemical castration of 20 ng/dL was only reached in approximately 43% of the men. The level of free T that was found to correspond to this level of total T was 0.5 pg/mL, and 43% of the men on LHRH were similarly below this level (Morote et al., Int J Biomarkers, 20:119-122, 2005).
Primary ADT, which causes castration (serum total testosterone levels of <50 ng/dL), is used to initially treat patients with metastatic hormone naïve prostate cancer. Symptoms improve with ADT, but ADT does not cure these patients. Unfortunately, prostate cancer cells eventually become castration resistant and these men develop progressive disease. Men with mCRPC have a very poor prognosis, severe cancer related symptoms, and a life expectancy of less than 16 months.
In males Androgen Deprivation Therapy not only reduces testosterone levels, but also estrogen levels, since estrogen is derived from the aromatization of testosterone, which levels are depleted by ADT. As a result, ADT also reduces estrogen to “castrate” levels.
Androgen deprivation therapy-induced estrogen deficiency causes significant side effects which include hot flashes, gynecomastia and mastalgia, bone loss, decreases in bone quality and strength, osteoporosis and life-threatening fractures, adverse lipid changes and higher cardiovascular disease and myocardial infarction, and depression and other mood changes. It is believed that many of the estrogen deficiency side effects of ADT are mediated by ERα.
Leuprolide acetate (Lupron®) is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LHRH). Leuprolide acetate is an LHRH superagonist that eventually suppresses LH secretion by the pituitary. Leuprolide acetate acts as a potent inhibitor of gonadotropin secretion, resulting in suppression of ovarian and testicular steroidogenesis. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels (below 50 ng/dL). In premenopausal females, estrogens are reduced to postmenopausal levels. Testosterone is a known stimulus for cancerous cells of the prostate. Suppressing testosterone secretion or inhibiting the actions of testosterone is thus a necessary component of prostate cancer therapy. Leuprolide acetate can be used for LH suppression, which is the reduction and lowering of serum testosterone to castrate levels to treat prostate cancer.
Prior to the introduction of LHRH agonists, castrate testosterone levels were achieved by increasing estrogen activity in the pituitary via estrogens, primarily diethylstilbestrol (DES). DES was equally effective as LHRH agonists at suppressing testosterone to castrate levels. Patients treated with DES did not have hot flashes or bone loss, but did have gynecomastia at higher rates than ADT with LHRH agonists. Unfortunately, highly potent, pure estrogens, like DES and estradiol, are often associated with a high risk of severe cardiovascular and thromboembolic complications which have limited their clinical use.
The compounds of this invention are nonsteroidal selective ERα agonists. In the treatment of CRPC and metastatic CRPC (mCRPC) patients, these novel small molecules further suppress testosterone levels for patients on ADT (i.e., these patients' testosterone levels are already at castrate levels) by increasing levels of serum sex or steroidal hormone binding globulin (SHBG) thereby reducing the circulating levels of serum free testosterone, the form of testosterone that stimulates prostate growth and prostate cancer. Because they are ERα agonists, the compounds of this invention also improve the side effects of estrogen deficiency including the ability to maintain bone, reduce the incidence of hot flashes, and avoid the insulin resistance and adverse lipid changes that are commonly associated with LHRH agonists and antagonists.